JP2021502178A - In-line droplet delivery device with a small volume ampoule and electrically actuated by breathing and how to use - Google Patents

Abstract

A droplet delivery device with a small volume drug ampoule for delivering an accurate and reproducible dose for lung use to a subject and related methods are disclosed. The droplet delivery device is configured to facilitate the ejection of small amounts, eg, single-use therapeutic agents. The droplet delivery device includes a housing, a mouthpiece, a small volume drug ampoule, an ejector mechanism, and at least one differential pressure sensor. The differential pressure sensor senses a predetermined pressure change in the housing and the delivery device is automatically breathed by the user. The droplet delivery device is then activated to generate a droplet plume with an average ejection particle diameter within the breathable size range, eg, less than about 5-6 μm, to target the user's lung system. .. The small volume drug solution ampoule may include a reservoir with an internal flexible membrane that separates the two internal volumes of a first background pressure fluid volume and a second drug solution volume. [Selection diagram] FIG. 1B

Description

Related application
[0001] This application relates to US Provisional Patent Application No. 62 / 583,310 entitled "ELECTRONIC BREATH ACTUATED IN-LINE DROPLET DELIVERY DEVICE WITH SINGLE USE AMPOULE AND METHODS OF USE" filed on November 8, 2017. Claims priority under 35 USC 119. The contents of each application are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to a droplet delivery device, and more specifically to a droplet delivery device for delivering a fluid to the lung system.

[0003] The use of aerosol generators for the treatment of various respiratory illnesses is an area of great interest. Inhalation provides delivery of aerosolized drugs for the treatment of asthma, COPD, and site-specific conditions with reduced adverse effects on the entire body. A key challenge is to provide a device that delivers accurate, consistent, and verifiable doses of droplet size suitable for successful delivery of the drug to the target lung passage.

[0004] Accurate dose confirmation, delivery, and inhalation of the dosage at a given time is important. Getting the patient to use the inhaler correctly is also a major issue. There is a need to ensure that patients use the inhaler correctly and take the right dosage at the given time. Problems arise when patients misuse or mistakenly take dosages. Unexpected results occur when the patient does not feel the benefit and stops taking the drug, or does not feel the expected benefit, or overuses the drug to increase the risk of excessive dosage. Physicians also face problems in interpreting and diagnosing prescribed treatments when treatment results are not available.

[0005] Currently, many inhaler systems, such as metered dose inhalers (MDI) and pressurized metered dose inhalers (p-MDI) or pneumatic and ultrasonic driven devices, are fast and have high momentum and motion. Produces a wide range of droplet sizes, including large droplets with energy. Droplets and aerosols with such high momentum do not reach the distal lungs or lower lung passages, but rather deposit in the mouth and throat. As a result, higher total drug doses are needed to achieve the desired deposition in the targeted lung area. These high doses increase the likelihood of unwanted side effects.

[0006] Aerosol plumes produced from current aerosol delivery systems are subject to local cooling to the device surface, followed by condensation, adhesion, and crystallization due to their high ejection speed and rapid expansion of the drug transport propellant. Can bring about crystallization. Blockage of the device surface by deposited drug residues is also a problem.

[0007] This phenomenon of surface condensation is also a challenge for existing vibrating mesh or aperture plate atomizers on the market. In these systems, manufacturers require disinfection after a single use to prevent potential microbial contamination, as well as frequent cleaning and cleaning to prevent drug buildup on the mesh aperture surface. And. Another challenge is that delivery of viscous drugs and suspensions can clog apertures or pores, leading to inefficiencies or inaccuracies in delivery of drug solutions to patients, or inoperability of the device. Also, the use of cleaning agents or other cleaning or sterilizing fluids causes deterioration of the ejector mechanism or other parts of the atomizer, and there is uncertainty about the ability or operating condition of the device to provide the correct dose to the patient. Can bring.

[0008] Therefore, there is a need for a droplet delivery device that can deliver a verifiable amount of droplets in an appropriate size range and avoid fluid buildup on the surface and aperture blockage, as well as patients and physicians. There is a need for a droplet delivery device that can provide professionals such as pharmacists, or therapists with feedback on the accurate and consistent use of the device.

[0009] Outline of the invention
[0010] In one aspect, the present disclosure relates to an exhalation-actuated droplet delivery device for delivering a fluid as a discharge stream of droplets to a subject's lung system. In certain embodiments, the droplet delivery device is configured such that the housing, its internal components, and various device components (eg, mouthpiece, air inlet flow element, etc.) are substantially in-line or parallel (eg, air). Oriented (along the flow path) and configured to form a small handheld device. In certain embodiments, the droplet delivery device is configured to facilitate ejection of a small amount of therapeutic agent, eg, a single-use volume.

[0011] In certain embodiments, the droplet delivery device is in the housing, including a housing, a mouthpiece located at the air outlet of the housing, and a drug solution storage for receiving a small amount of fluid. It is a small-capacity chemical solution amplifier arranged so as to communicate with the housing and an ejector mechanism for fluid communication with the storage portion, and includes a piezoelectric actuator and an aperture plate, and the aperture plate is formed through the thickness thereof. The piezoelectric actuator has an ejector mechanism that vibrates the aperture plate to generate a discharge flow of the droplet, and at least one differential pressure sensor arranged in the housing. The differential pressure sensor is configured to activate the ejector mechanism when it senses a predetermined pressure change in the mouthpiece, thereby generating a discharge flow of droplets, the ejector mechanism. At least about 50% of the droplet is less than about 6 microns so that at least about 50% of the mass of the droplet eruption stream is delivered to the subject's lung system in a breathable range during use. It is configured to generate an emission stream of said droplet having an average emission droplet diameter. In certain embodiments, the small volume drug ampoule may include a reservoir with an internal flexible membrane that separates the two internal volumes, a first background pressure fluid volume and a second internal volume.

[0012] In some embodiments, the droplet delivery device is an air inlet flow element located within the air flow at the device's air inlet and is a non-turbulent flow (ie, layer) across the outlet side of the aperture plate. An air inlet configured to facilitate flow and / or transitional air flow and to provide sufficient air flow to ensure that the droplet flow released during use flows through the droplet delivery device. It also includes a flow element. In some embodiments, the air inlet flow element may be located within the mouthpiece.

[0013] In certain embodiments, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is perpendicular to the direction of the airflow and the flow of droplets is emitted parallel to the direction of the airflow. To. In another embodiment, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is parallel to the direction of the airflow and the flow of droplets is emitted substantially perpendicular to the direction of the airflow. , The ejection stream is oriented with respect to the housing so that it changes its trajectory by about 90 degrees and is guided through the housing before it is ejected from the housing.

[0014] In yet another aspect, the reservoir of the droplet delivery device is detachably coupled to the housing. In another aspect, the reservoir of the droplet ejection device is coupled to the ejector mechanism to form a coupled reservoir / ejector mechanism module, and the coupled reservoir / ejector mechanism module is detachably coupled to the housing. Will be done.

[0015] In yet another aspect, the aperture plate of the droplet delivery device has a dome shape. In other embodiments, the aperture plate may be made of a metal such as stainless steel, nickel, cobalt, titanium, iridium, platinum, or palladium, or an alloy thereof. Alternatively, the plate may be made of a suitable material, including other metals or polymers. In certain embodiments, the aperture plate is, for example, polyetheretherketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultrahigh molecular weight polyethylene (UHMWPE), nickel, nickel cobalt, palladium, nickel palladium. , Platinum, or other suitable metal alloys, and combinations thereof. In another aspect, one or more of the openings in the aperture plate have different cross-sectional shapes or diameters, thereby providing emission droplets with different average emission droplet diameters.

[0016] In yet another aspect, the reservoir of the droplet delivery device is detachably coupled to the housing. In another aspect, the reservoir of the droplet ejection device is coupled to the ejector mechanism to form a coupled reservoir / ejector mechanism module, and the coupled reservoir / ejector mechanism module is detachably coupled to the housing. Will be done.

[0017] In another aspect, the droplet delivery device may further include a wireless communication module. In some embodiments, the wireless communication module is a Bluetooth® transmitter.

[0018] In yet another aspect, the droplet delivery device may further comprise one or more sensors selected from an infrared transmitter, a photodetector, an additional pressure sensor, and a combination thereof.

[0019] In one aspect, the present disclosure relates to a method of generating and delivering a fluid within the respirable range to a subject's lung system as a flow of droplets. The method comprises: (a) generating a discharge stream of droplets, at least about 50% having an average discharge droplet diameter of less than about 6 μm, via the exhalation actuated droplet delivery apparatus of the present disclosure. b) The step of delivering the droplet efflux to the subject's pulmonary system so that at least about 50% of the mass of the droplet effluent during use is delivered to the subject's pulmonary system within a breathable range. And, including.

[0020] In another aspect, the present disclosure relates to a method of delivering a therapeutic agent to a subject's lung system as a respiratory flow of droplets to treat a disease, disorder, or condition of the lung. The method comprises: (a) generating a discharge stream of droplets, at least about 50% having an average discharge droplet diameter of less than about 6 μm, via the exhalation actuated droplet delivery apparatus of the present disclosure. b) Discharge the droplets to the subject's lung system so that at least about 50% of the mass of the droplet eruption flow is delivered to the subject's lung system within a breathable range during use. Includes steps to deliver to and treat lung diseases, disorders, or conditions.

[0021] In certain embodiments, lung disease, disorder, or condition is selected from asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), tuberculosis, chronic bronchitis, and pneumonia. .. In another embodiment, the lung disease is lung cancer. In a further aspect, the therapeutic agent is a COPD drug, an asthma drug, or an antibiotic. Therapeutic agents can be selected from albuterol sulfate, ipratropium bromide, tobramycin, fluticasone propionate, fluticasone flocate, tiotropium, glycopyrrolate, olodaterol, salmeterol, umeclidinium, and combinations thereof. In yet another aspect, the therapeutic agent may be delivered to the subject's lung system at a reduced dosage compared to the dosage of an inhaler with standard propellant.

[0022] In yet another aspect, the present disclosure is for systemic delivery of a therapeutic agent as an exhalation of breathable droplets into a subject's lung system for the treatment of a disease, disorder, or condition. Regarding the method. This method involves (a) generating a discharge stream of droplets, at least about 50% having an average discharge droplet diameter of less than about 6 μm, via a piezoelectrically actuated droplet delivery device, and (b) use. The droplet discharge is delivered to the subject's lung system so that at least about 50% of the mass of the droplet discharge is delivered to the subject's lung system within a breathable range. Includes the step of forward delivery of a therapeutic agent to a subject to treat a disease, disorder, or condition.

[0023] In certain embodiments, the disease, disorder, or condition is selected from true diabetes, rheumatoid arthritis, psoriasis vulgaris, Crohn's disease, hormone replacement therapy, neutropenia, nausea, and influenza.

[0024] In a further aspect, the therapeutic agent is a therapeutic peptide, protein, antibody, or other bioengineered molecule. In a further aspect, the therapeutic agent is a growth factor, insulin, vaccine, antibody, Fc fusion protein, hormone, enzyme, gene therapy and RNAi cell therapy, antibody-drug conjugate, cytokine, anti-infective agent, polynucleotide, oligonucleotide, Or select from any combination of them. In another aspect, the therapeutic agent is delivered to the subject's pulmonary system at a reduced dosage as compared to oral or intravenous medication.

[0025] A plurality of embodiments have been disclosed, and the following detailed description illustrating and illustrating exemplary embodiments of the present disclosure will reveal to those skilled in the art yet other embodiments of the present disclosure. Let's do it. It will be appreciated that the present invention can be modified in various ways without departing from the spirit and scope of the present disclosure. Therefore, the detailed description should be considered exemplary in nature and not limiting.

[0026] FIG. 1A shows a perspective view of an exemplary in-line droplet delivery device according to an embodiment of the present disclosure. FIG. 1B shows a perspective view of an exemplary in-line droplet delivery device according to an embodiment of the present disclosure. [0027] FIG. 2 is an enlarged view of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0028] FIG. 3A-1 is a partial perspective view of the base unit of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0029] FIG. 3A-2 is an enlarged view of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0030] FIG. 3B-1 is a bottom perspective view of a drug solution delivery ampoule of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0031] FIG. 3B-2 is an enlarged view of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0032] FIGS. 3C-1, 3C-2, and 3C-3 are cross-sectional perspective views of the in-line droplet delivery device of FIGS. 1A and 1B according to an embodiment of the present disclosure. [0033] FIG. 4A shows a perspective view of another example of an in-line droplet delivery device according to an embodiment of the present disclosure. FIG. 4B shows a perspective view of another example of an in-line droplet delivery device according to an embodiment of the present disclosure. [0034] FIG. 5 is an enlarged view of the in-line droplet delivery device of FIGS. 4A and 4B according to an embodiment of the present disclosure. [0035] FIG. 6 is a cross-sectional perspective view of the in-line droplet delivery device of FIGS. 4A and 4B according to an embodiment of the present disclosure. [0036] FIG. 7 is a perspective view of the in-line droplet delivery device of FIGS. 4A and 4B, which does not include a drug solution delivery ampoule according to an embodiment of the present disclosure. [0037] FIG. 8A is a perspective view showing the front surface of the drug solution delivery ampoule and the mouthpiece cover according to the embodiment of the present disclosure. FIG. 8B is a perspective view showing the back surface of the drug solution delivery ampoule and the mouthpiece cover according to the embodiment of the present disclosure. [0038] FIG. 9 is a cross-sectional view of an exemplary small volume chemical ampoule according to an embodiment of the present disclosure. [0039] FIG. 10A is a perspective view showing an alternative drug solution delivery ampoule. FIG. 10B is an enlarged top view showing an alternative drug solution delivery ampoule. FIG. 10C is an enlarged bottom view showing an alternative drug solution delivery ampoule. [0040] FIG. 11A is a portion of the in-line droplet layer thickness apparatus of FIGS. 1A and 1B comprising a drug solution delivery ampoule, a mouthpiece including an inlet flow element, and a mouthpiece cover according to an embodiment of the present disclosure. It is a cross-sectional perspective view. [0041] FIG. 11B is a front view of the in-line droplet layer thickness apparatus of FIGS. 1A and 1B comprising a drug solution delivery ampoule and a mouthpiece including an inlet flow element according to an embodiment of the present disclosure. [0042] FIG. 11C is a front view of the components of the in-line droplet layer thickness device of FIGS. 1A and 1B including a mouthpiece and an internal housing according to an embodiment of the present disclosure. [0043] FIG. 12A is a plot of differential pressure as a function of flow rate through an exemplary inlet flow element as a function of the number of holes, according to one embodiment of the present disclosure. FIG. 12B shows the differential pressure as a function of the flow rate through an exemplary inlet flow element as a function of 17 holes having a constant screen hole size and number of holes according to an embodiment of the present disclosure. It is a plot of. [0045] FIG. 13A shows an exemplary drug solution delivery ampoule having a mouthpiece joined to the air outlet side of the device according to an embodiment of the present disclosure. FIG. 13B shows a front sectional view. FIG. 13C shows a side sectional view. FIG. 13D shows the same figure with exemplary dimensions. [0046] FIG. 14A shows an alternative drug solution delivery ampoule with a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. FIG. 14B shows a front sectional view. FIG. 14C shows a side sectional view. FIG. 14D shows the same figure with exemplary dimensions. FIG. 15A shows an alternative drug solution delivery ampoule with a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. FIG. 15B shows a front sectional view. FIG. 15C shows a side sectional view. FIG. 15D shows the same figure with exemplary dimensions. [0048] FIG. 16A shows an exemplary drug solution delivery ampoule having a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. The mouthpiece includes two air inlets on the outside of the mouthpiece and two internal baffles with additional air inlets to provide resistance and modeling to airflow. FIG. 16B shows a front sectional view. FIG. 16C shows a side sectional view. FIG. 16D shows the same figure with exemplary dimensions. FIG. 17A shows an exemplary drug solution delivery ampoule with a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. The mouthpiece includes two air inlets on the outside of the mouthpiece and two internal baffles with additional air inlets to provide resistance and modeling to airflow. FIG. 17B shows a front sectional view. FIG. 17C shows a side sectional view. FIG. 17D shows the same figure with exemplary dimensions. [0050] FIG. 18A shows an exemplary drug solution delivery ampoule with a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. The mouthpiece consists of two substantially concentric internal baffles (two arcs forming a circle at the top and bottom of the mouthpiece) with two air inlets on the outside of the mouthpiece and two additional air inlets. ), Includes, and provides resistance to airflow and modeling. FIG. 18B shows a front sectional view. FIG. 18C shows a side sectional view. FIG. 18D shows the same figure with exemplary dimensions. [0051] FIG. 19A shows an exemplary drug solution delivery ampoule having a mouthpiece joined to the air outlet side of the device according to an embodiment of the present disclosure. The mouthpiece consists of two air inlets on the outside of the mouthpiece and two substantially concentric internal baffles (two arcs forming a circle at the top and bottom of the mouthpiece) with four air inlets. , Including resistance to airflow and modeling. FIG. 19B shows a front sectional view. FIG. 19C shows a side sectional view. FIG. 19D shows the same figure with exemplary dimensions. [0052] FIG. 20A shows an exemplary drug solution delivery ampoule with a mouthpiece joined to the air outlet side of the device according to one embodiment of the present disclosure. The mouthpiece includes two air inlets on the outside of the mouthpiece and two substantially concentric internal baffles with two additional air inlets to provide resistance to airflow and modeling. In addition, the internal region of the mouthpiece between the concentric baffles and the wall of the mouthpiece contains array elements located above the air inlet, providing additional resistance and modeling to the air flow. The array elements are arranged parallel to the direction of the air flow. FIG. 20B shows a front sectional view. FIG. 20C shows a side sectional view. FIG. 20D shows the same figure with exemplary dimensions. [0053] FIG. 21 is a plot of spray efficiency as a function of flow rate through an exemplary air inlet flow element as a function of number and configuration of openings, baffles, etc., according to an embodiment of the present disclosure. [0054] FIG. 22A is an end view showing an exemplary aperture plate sealing mechanism according to an embodiment of the present disclosure. FIG. 22B is a side view showing an exemplary aperture plate sealing mechanism according to an embodiment of the present disclosure. FIG. 22C is a side view showing an exemplary aperture plate sealing mechanism according to an embodiment of the present disclosure. FIG. 22D shows an alternative embodiment in which the mouthpiece cover includes an aperture plate plug.

Effective delivery of the drug through the alveoli to the deep lung region of the lung has always been a problem, especially for children and the elderly with limited lung capacity and narrowing of the respiratory channel and patients with morbidity. Will be done. The narrowed pulmonary passages limit deep inspiration and limit synchronization of the dose administered with the inspiratory / expiratory cycle. For optimal deposition in the alveolar airways, droplets with aerodynamic diameters in the range of 1-5 μm are optimal, and droplets less than about 4 μm effectively reach the alveolar region of the lung. In contrast, droplets larger than about 6 μm deposit on the tongue or are struck in the throat and cover the bronchial passages. Smaller droplets that penetrate deeper into the lungs, eg, less than about 1 μm, tend to be exhaled.

[0056] A particular aspect of the present disclosure is electrical for delivery of an inhalation therapeutic agent, as described herein as an in-line droplet delivery device or a soft mist inhaler (SMI) device with a small volume drug solution amplifier. Fully digital platform. In some embodiments, the small ampoule is a disposable ampoule (single ampoule). This device provides significant improvements to current inhalation delivery systems by improving dosing accuracy, dosing reliability, and patient delivery. In certain embodiments, the devices of the present disclosure include fully integrated monitoring capabilities designed to enhance compliance and ultimately reduce disease-related morbidity.

[0057] In certain embodiments, the present disclosure includes an in-line droplet delivery device with a small volume drug ampoule for delivering a fluid to the subject's lung system as a flow of droplets, and a safe, appropriate, subject. Relevant methods for delivering repeatable drug doses to a person's lung system. The disclosure also presents in the form of a flow of droplets that is appropriate, repeatable and in use such that a high proportion of droplets is delivered to a desired location within the airways, eg, the subject's alveolar airways. Includes a drop delivery device and system with a small volume drug solution ample capable of delivering a fixed amount of fluid.

[0058] The present disclosure provides an in-line droplet delivery device with a small volume drug solution ampoule for delivering a fluid to the subject's lung system as a flow of droplets, the device comprising a housing and a mouthpiece. A small volume chemical ampoule containing a chemical reservoir for storing a small amount of fluid and an ejector mechanism including a piezoelectric actuator and an aperture plate, the ejector mechanism being less than about 6 microns, preferably less than 5 microns. It is configured to eject a stream of droplets having an average ampoule diameter of.

[0059] In certain embodiments, the small volume drug ampoule may be configured as a single use ampoule (eg, disposable on a daily or use basis). Such embodiments are particularly useful in therapeutic agents that are sensitive to storage conditions, such as, for example, degradation, aggregation, structural changes, and contamination sensitivity. In this regard, small volume chemical ampoules allow for aseptic storage of therapeutic agents under suitable conditions until use, such as in a temperature controlled environment, as a powder for reconstruction. As a non-limiting example, the small volume drug ampoules of the present disclosure are particularly suitable for use in therapeutic peptides, proteins, antibodies, other bioengineering molecules, or biologics. However, the present disclosure is not so limited, and small volume drug ampoules can be used with any therapeutic agent known in the art.

[0060] Although not intended to be limited to theory, in certain embodiments, the small volume drug ampoules of the present disclosure, for example, have a limited period of use that minimizes fluid evaporation in the reservoir. Compared to large capacity / versatile ampoules, in terms of minimizing the possibility of fluid contamination in the reservoir and / or the surface of the ejector, and minimizing the amount of time the ampoule is held in uncontrolled storage. Can also provide benefits.

[0061] In certain embodiments, the small volume drug ampoule is a small volume fluid, eg, a dose of 10 or less, a dose of 5 or less, a dose of 4 or less, a dose of 3 or less, a dose of 2 or less. Includes a fluid storage for accepting single doses. Small volume drug ampoules are configured to facilitate the ejection of small doses, eg, single-use therapeutic agents. As described in more detail herein, a small volume chemical ampoule is a reservoir with an internal flexible membrane that separates two internal volumes, a first background pressure fluid volume and a second chemical volume. May include. In certain embodiments, the flexible membrane is such that the background pressure fluid volume creates a fluid area behind / above the drug solution volume without allowing mixing or dilution of the therapeutic agent with the background pressure fluid. Separate the two volumes. Small volume drug ampoules may further include an air exchange vent or air space configured in the area of background pressure fluid volume to prevent or reduce the generation of negative pressure during ejection of the drug fluid in use. As described herein, the air exchange vent may optionally include a superhydrophobic filter in combination with a spiral vapor barrier, which allows free air in and out of the reservoir. it can.

As shown in more detail herein, the droplet delivery device is configured in an in-line arrangement with a housing, its internal components, and various device components (eg, mouthpiece, air inlet flow element). Etc.) are oriented in a substantially in-line or parallel configuration (eg, along the air flow path) to form a small handheld device. In certain embodiments, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is perpendicular to the direction of airflow and the flow of droplets is emitted parallel to the direction of airflow. In another embodiment, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is parallel to the direction of the airflow and the flow of droplets is emitted substantially perpendicular to the direction of the airflow. The ejected droplet flow is guided by changing its orbit by about 90 degrees before being ejected from the housing.

[0063] In certain embodiments, the ejector mechanism is located within the housing of the in-line droplet delivery device and is electrically actuated by breathing by at least one differential pressure sensor that detects a predetermined pressure change within the mouthpiece. To do. As described in more detail herein, in certain embodiments, such predetermined pressure changes may be detected during the intake cycle by the user of the device.

[0064] In some embodiments, the droplet delivery device is an air inlet flow element located within the air flow at the air inlet of the housing and is a non-turbulent flow (ie, layer) across the outlet side of the aperture plate. An air inlet configured to facilitate flow and / or transitional air flow and to provide sufficient air flow to ensure that the droplet flow released during use flows through the droplet delivery device. It also includes a flow element. In some embodiments, the air inlet flow element may be located within the mouthpiece. As described in more detail herein, the air inlet flow element may be placed along the direction of the airflow or in-line behind the outlet side of the aperture plate or along the direction of the airflow. It may be placed in front of the outlet side of the aperture plate. In certain embodiments, the air inlet flow element comprises one or more openings formed through it and configured to increase or decrease internal pressure resistance within the droplet delivery device during use. For example, an air inlet flow element comprises an array of one or more openings. In one embodiment, the air inlet flow element comprises one or more baffles, for example, one or more baffles include one or more air flow openings.

[0065] According to a particular aspect of the present disclosure, effective deposition in the lung generally requires droplets less than about 5-6 μm in diameter. Although not intended to be limited by theory, in order to deliver the fluid to the lungs, the droplet delivery device has sufficient momentum to allow ejection from the device and is tongue. Alternatively, the amount of exercise must be small enough to prevent it from accumulating in the back of the throat. Droplets less than about 5-6 μm in diameter are carried almost completely by the movement of the airflow and the movement of the mixed air carrying the droplets, not by their own motion.

[0066] In certain aspects, the present disclosure includes and provides an ejector mechanism configured to eject a flow of droplets within a breathable range of about 5-6 μm, preferably less than 5 μm. The ejector mechanism comprises an aperture plate that is directly or indirectly coupled to the piezoelectric actuator. In certain embodiments, the aperture plate may be coupled to an actuator plate coupled to a piezoelectric actuator. The aperture plate generally includes multiple openings formed through its thickness, and the piezoelectric actuator opens the aperture plate opening when the patient inhales the aperture plate with fluid that contacts one surface of the aperture plate. Vibrate directly or indirectly (eg, through an actuator plate) at a frequency and voltage that creates a directional aerosol flow of droplets through and into the lung. In another embodiment in which the aperture plate is coupled to the actuator plate, the actuator plate is vibrated by a piezoelectric oscillator at a frequency and voltage that produces a directional aerosol stream or plume of aerosol droplets.

[0067] In certain aspects, the present disclosure relates to an in-line droplet delivery device for delivering a fluid to a subject's lung system as a flow of droplets with a small volume drug solution ampoule. Droplet discharge streams include, but are not limited to, solutions, suspensions, or emulsions having a viscosity that allows the droplets to be formed using an ejector mechanism. In certain aspects, the therapeutic agent can be delivered at higher dose concentrations and higher efficacy compared to alternative routes of administration and standard inhalation techniques.

[0068] More specifically, using an in-line droplet delivery device with a small volume drug ampoule, it comprises small molecules, therapeutic peptides, proteins, antibodies, and other bioengineering molecules via the pulmonary system. For local or systemic delivery of the therapeutic agent, the therapeutic agent can be delivered to the subject's lung system with an ampoule as an eruption stream. In some embodiments, an in-line droplet delivery device can be used to deliver therapeutic agents for the treatment or prevention of cancer, including lung cancer, locally or systemically. As a non-limiting example, an in-line droplet delivery device can be used to treat or prevent signs of inducing, for example, true diabetes, rheumatoid arthritis, plaque psoriasis, Crohn's disease, hormone replacement, neutropenia, nausea, influenza, etc. Can be used to systematically deliver therapeutic agents for.

[0069] As a non-limiting example, therapeutic peptides, proteins, antibodies, and other bioengineering molecules include insulin, vaccines (Prevnor-Pneumonia, Gardasil-HPV), antibodies (Keitruda) (pembrolizumab). )), Opdivo (nivolumab), Avastin (bevacizumab), Humira (adalimumab), Remicade (Remiced), Remiced (Remiced) ) (Trustuzumab)), Fc fusion protein (Enbrel (etanercept), Orencia (Abatacept)), Hormone (Elomba, long-acting F) Hormones), enzymes (Plumozime-rHu-DNAase-), other proteins (coagulation factors, interleukin, albumin), gene therapy and RNAi, cell therapy (Provenge-prostatic cancer vaccine), antibody drug conjugate-adsetris (Conjugates-adcetris (Brentuximab vedotin for HL) cytokines, anti-infective agents, polynucleotides, oligonucleotides (eg, gene vectors), or any combination thereof, or Flonase ) (Fruticazone propionate) or Advia (fluticazone propionic acid and salmeterol xinafoic acid) containing solid droplets or suspensions.

[0070] In other embodiments, an in-line droplet delivery device with a small volume drug solution ampol, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), tuberculosis, chronic bronchitis, or pneumonia. Can be used for the treatment or prevention of lung disease or disorder. In certain embodiments, the in-line droplet delivery device can be used to deliver a therapeutic agent such as a COPD drug, an asthma drug, or an antibiotic. As a non-limiting example, such therapeutic agents include albuterol sulfate, ipratropium bromide, tobramycin, fluticasone propionate, fluticasone flocate, tiotropium, glycopyrrolate, olodaterol, salmeterol, umeclidinium, and combinations thereof. Can be done.

[0071] In another embodiment, the in-line droplet delivery device with the small volume drug solution ampols of the present disclosure is a highly controlled dosage for smoking cessation or a condition required for medical or veterinary treatment. For delivery, it can be used to deliver a nicotine solution containing a water-nicotine azeotropic mixture. In addition, the fluid may contain THC, CBD, or other chemicals found in marijuana for the treatment of seizures and other conditions.

[0072] In certain embodiments, an in-line drug delivery device with a small volume drug ampoule of the present disclosure is a regular such as a drug for highly controlled dosing of a monitored or otherwise controlled analgesic. And may be used to deliver controlled substances. In certain embodiments, as a non-limiting example, medication may only be possible by instructions to the device by a doctor or pharmacist, such as the patient's place of residence as confirmed by the GPS position on the patient's smartphone. Dosing may be enabled only in certain locations of the drug, or may be controlled by monitoring compliance with dosing schedules, doses, abuse compliance, etc. In certain embodiments, this mechanism of highly controlled dosing of controlled agents can prevent abuse or overdose of controlled substances.

Specific advantages of the lung pathway for delivery of drugs and other pharmaceuticals include a non-invasive, needle-free delivery system suitable for delivery of a wide range of substances ranging from small molecules to very large proteins. , A low level of metabolic enzyme compared to the gastrointestinal tract, including that absorbed molecules do not produce a first pass effect. (A. Tronde et al., J Pharm Sci, 92 (2003) 1216-1233; A.L. Adjei et al .., Inhalation Delivery of Therapeutic Peptides and Proteins, M. Dekker, New York, 1997). In addition, drugs that are administered orally or intravenously are diluted throughout the body, but by direct administration of the drug to the lungs, the target site (lung) is about 100 times greater than the same intravenous dosage. High concentrations can be provided. This is particularly important for the treatment of drug-resistant bacteria, drug-resistant tuberculosis, for example, and is important for coping with drug-resistant bacterial infections, which is an increasing problem in ICU.

Another advantage of administering the drug directly to the lungs is that side effects associated with high toxicity levels of the drug in the bloodstream can be minimized. For example, intravenous tobramycin is restricted in its use because it leads to very high blood levels that are toxic to the kidneys, but inhaled medications in the lungs without severe side effects on renal function. Significantly improve function. (Ramse et al., Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340: 23-30; MacLusky et al., Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa Pediatr Pulmonol 1989; 7: 42-48; Geller et al., Pharmacokinetics and bioavailablility of aerosolized tobramycin in cystic fibrosis. Chest 2002; 122: 219-226.)

[0075] As mentioned above, for effective delivery of droplets deep into the pulmonary airways, droplets less than about 5-6 microns in diameter, specifically mass average aerodynamic diameter less than about 5 microns. A droplet having (MMAD) is required. The mass average aerodynamic diameter is defined as a diameter where 50% of the droplets by mass are larger and 50% are smaller. In certain aspects of the disclosure, droplets in this size range are high enough to allow release from the device for deposition in the alveolar airways, but overcome deposits on the tongue (soft palate) or throat. Must have enough momentum to do.

[0076] In another aspect of the present disclosure, a method is provided for using the droplet delivery apparatus of the present disclosure to generate a discharge stream of droplets for delivery to the user's lung system. In certain embodiments, the droplet eruption flow is generated within a controllable and defined droplet size range. As an example, the droplet size range is at least about 50%, at least about 60%, at least about 70%, at least about 85%, at least about 90%, about 50% to about 90%, about 60 of the ejected droplets. % To about 90%, about 70% to about 90%, about 70% to about 95%, etc. are in a breathable range of about 6 μm, preferably less than about 5 μm.

[0077] In other embodiments, the droplet eruption flow has multiple diameters because it targets multiple areas of the airways (mouth, tongue, throat, upper airways, lower respiratory tract, deep lungs, etc.). It may have one or more diameters so that droplets are produced. As an example, the droplet diameter is about 1 μm or more and about 200 μm or less, about 2 μm or more and about 100 μm or less, about 2 μm or more and about 60 μm or less, about 2 μm or more and about 40 μm or less, about 2 μm or more and about 20 μm or less, about 1 μm or more, about 5 μm or less. , About 1 μm or more and about 4.7 μm or less, about 1 μm or more and about 4 μm or less, about 10 μm or more and about 40 μm or less, about 10 μm or more and about 20 μm or less, about 5 μm or more and about 10 μm or less, and combinations thereof. In certain embodiments, at least a portion of the droplet has a breathable range diameter, while other droplets may have other size diameters to target non-breathable locations (eg,). Larger than about 5 μm). The droplet stream exemplified in this regard has 50% to 70% droplets in the respirable range (less than about 5 μm) and is out of the respirable range (about 5 μm or more and about 10 μm or less, about 5 μm or more). It may have 30% to 50% droplets (eg, about 20 μm or less).

[0078] In another embodiment, the droplet delivery apparatus of the present disclosure is used to provide a method for delivering a safe, appropriate and repeatable dose of a drug to the pulmonary system. The method delivers a flow of droplets to desired locations in the subject's lung system, including deep lungs and the alveolar airways.

[0079] In a particular aspect of the present disclosure, an in-line droplet delivery device is provided for delivering a droplet discharge stream to a subject's lung system with a small volume drug solution ampoule. An in-line droplet feeder with a small volume drug solution amplifier is generally located within the housing, including a housing, a mouthpiece located on the air outlet side of the housing, and a drug solution storage for receiving a small amount of fluid. Alternatively, it includes a small volume chemical amplifier that fluidly communicates with the housing, an ejector mechanism that fluidly communicates with the reservoir, and at least one differential pressure sensor located within the housing. In certain embodiments, the small volume drug ampoule may include a reservoir containing an internal flexible membrane that separates the two internal volumes of a first background pressure fluid volume and a second drug solution volume. The housing, its internal components, and various device components (eg, mouthpieces, air inlet flow components, etc.) are configured substantially in-line or in parallel (eg, air flow paths) to form a small handheld device. (Along with). The differential pressure sensor is configured to activate the ejector mechanism when it detects a predetermined pressure change in the housing, and the ejector mechanism is configured to generate a controllable plume of droplet ejection flow.

[0080] In certain embodiments, the mouthpiece can be joined to the housing (and optionally removable and / or replaceable), integrated into the housing, or made part of the housing. In other embodiments, the mouthpiece can be joined to the drug solution delivery ampoule (and optionally removable and / or replaceable), integrated into the drug solution delivery ampoule, or part of the drug solution delivery ampoule. ..

[0081] Droplet evacuation streams include, but are not limited to, solutions, suspensions, or emulsions having viscosities that allow the droplets to be formed using an ejector mechanism. The ejector mechanism may include a piezoelectric actuator directly or indirectly coupled to an aperture plate having multiple openings formed through its thickness. Piezoelectric actuators can operate to vibrate the aperture plate directly or indirectly at frequency, thereby producing a flow of droplets.

[0082] In certain embodiments, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is perpendicular to the direction of the airflow and the droplet flow is emitted parallel to the direction of the airflow. In another embodiment, the housing and ejector mechanism are oriented such that the outlet side of the aperture plate is parallel to the direction of the airflow and the droplet flow is emitted substantially perpendicular to the direction of the airflow. The droplet eruption flow is guided through the housing in a change of about 90 degrees before being released from the housing.

[0083] In certain embodiments, an in-line droplet delivery device with a small volume drug solution ampoule has an ejector mechanism (eg, a storage / ejector mechanism module combination) embedded within the surface of the drug solution reservoir. It consists of a separate small volume drug delivery ampoule and a handheld base unit (eg housing) that includes a differential pressure sensor, a microprocessor, and three AAA batteries. In certain embodiments, the handheld base unit also includes a mouthpiece (optionally removable), an optional mouthpiece cover, and an optional ejector plate seal. The microprocessor controls volume delivery, volume measurement, and software design monitoring parameters that can be transmitted via Bluetooth® technology. The ejector mechanism optimizes the delivery of droplets to the lungs by creating a flow of droplets emitted in a predefined range with a high degree of accuracy and reproducibility. Early droplet studies have shown that at least 65% to 70% of the droplets ejected from the device are in the breathable range (such as 1-5 μm).

[0084] In certain embodiments, the in-line droplet delivery device with a small volume drug solution ampoule is suitable for prescription or over-the-counter drugs on a periodic basis, such as daily, weekly, monthly, or as needed. A replaceable or disposable combined storage / ejector mechanism module (eg, a small volume drug solution delivery ampoule) may be included. The reservoir may be pre-filled and stored in a pharmacy for dosing to the patient by using a suitable infusion means such as a hollow infusion syringe driven manually or by a micropump, or the pharmacy or It may be filled elsewhere. The syringe may fill the reservoir by pumping fluid into or from a rigid container or other foldable or non-foldable container. In certain embodiments, these disposable / replaceable combined reservoir / ejector mechanism modules can be used to minimize and prevent the accumulation of surface deposits or surface microbial contamination on the aperture plate due to their short usage time. ..

[0085] In certain aspects of the disclosure, the ejector mechanism, small volume drug reservoir, and housing / mouthpiece function to produce a plume with a droplet diameter of less than about 5 μm. As mentioned above, in certain embodiments, the small volume drug solution storage and ejector mechanism modules are powered by electronic devices within the device housing and storage to provide single doses, multiple doses, or hundreds of doses. Can carry sufficient chemicals.

[0086] The present disclosure also provides an in-line droplet delivery device having a small volume chemical ampoule and being highly unaffected by the place of use. In certain embodiments, an in-line droplet delivery device with a small volume drug ampoule occurs when the user moves from sea level to sea and high altitude, for example while traveling on an airplane where pressure differences greater than 4 psi can exist. It is configured so that it is not affected by the pressure difference obtained. As described in more detail herein, in certain embodiments of the present disclosure, the in-line droplet delivery device moves in and out of the reservoir while blocking moisture or fluid from passing into and out of the reservoir. A superhydrophobic filter that provides free exchange of air is optionally included with a spiral vapor barrier, which reduces or prevents fluid leakage or deposition on the surface of the aperture plate.

[0087] In certain embodiments, the apparatus of the present disclosure eliminates the need for patient / device adjustment by initiating a piezoelectric ejector in response to the onset of inhalation using a differential pressure sensor. The device does not require manual initiation of drug solution delivery. Unlike jet-driven MDI, droplets from the devices of the present disclosure are produced with little or no proper velocity from the aerosol formation process and are inhaled into the lungs only by the user's inspiration through the mouthpiece. The droplets ride on the mixed air and their deposition in the lungs is improved.

[0088] In certain embodiments, as described in more detail herein, when the drug solution ampoule is coupled to the handheld base unit, the base, including the battery, and the ejector mechanism embedded in the drug solution storage. There is an electrical contact between them. In certain embodiments, a visual display, such as a horizontal display of a series of three user-visible LED lights, and a voice display via a small speaker within the handheld base unit may provide user notification. As an example, the device can be, for example, 2.0-3.5 cm in height, 5-7 cm in width, 10.5-12 cm in length, about 95 grams with an empty chemical ampoule and battery inserted. Can be the weight of.

[0089] As described herein, in certain embodiments, an in-line droplet delivery device with a small volume drug solution ampoule inserts the drug solution ampoule into the base unit, opens the mouthpiece cover, and It can be activated and activated for use by switching the / or on / off switch / slide bar. In certain embodiments, visual and / or audio indicators can be used to indicate the status of the device, such as on, off, standby, ready, and so on. As an example, one or more LED lights may be lit and / or blinking in green or green to indicate that the device is available. In other embodiments, visual and / or audio indicators can be used to indicate the condition of the drug solution ampoule, including the number of doses taken, the number of remaining doses, instructions for use, and the like. For example, an LED visual screen may show a dosing counter numerical display showing the remaining dosage in the reservoir.

[0090] As described in more detail herein, during use, the differential pressure sensor in the housing is inhaled by the user through the mouthpiece of the housing of the inline droplet delivery device of the present disclosure, for example, the rear of the mouthpiece. Inspiratory flow is detected by measuring the pressure drop across the Venturi plate at. When a threshold pressure drop (eg, 8 slm) is achieved, the microprocessor activates an ejector mechanism to generate a discharge stream of droplets into the air stream of the device that the user inhales through the mouthpiece. In certain embodiments, audio and / or visual indicators may be used to indicate that medication has begun, eg, one or more LEDs may be lit green. The microprocessor then shuts down the ejector at a specified time after the start to achieve the desired dosage, eg 1-1.45 seconds. In certain embodiments, as described in more detail herein, the device may be provided with visual and / or audio indicators that facilitate proper dosing, eg, the device is affirmed after the start of dosing. You may instruct them to start holding their breath for a specified time, eg, 10 seconds, by making a chime sound. During the period of holding your breath, for example, three green LEDs may blink. In addition, there may be voice commands instructing the patient to exhale, inhale, and hold the breath at the appropriate time using the audio indicator of the respiratory arrest countdown.

Following dosing, an in-line droplet delivery device with a small volume drug ampoule may, for example, close the mouthpiece cover, switch on / off / slide bar, time out from non-use, remove the drug ampoule. It may be turned off and stopped by any suitable method. If necessary, audio and / or visual indicators prompt the user to stop the device, such as by blinking one or more red LED lights or providing a voice command to close the mouthpiece cover. May be good.

[0092] In certain embodiments, an in-line droplet delivery device with a small volume drug ampoule seals the aperture plate to protect the condition of the aperture plate when not in use, minimizing fluid contamination and evaporation inside the reservoir. It may include an ejector mechanism closure system to prevent and prevent. For example, in some embodiments, the device may include a mouthpiece cover that includes a rubber plug of a size and shape that seals the outlet side of the aperture plate when the cover is closed. In other embodiments, the mouthpiece cover may cause a slide to seal the outlet side of the aperture plate when the cover is closed. Other embodiments and configurations such as manual slides, covers, and plugs are also envisioned. In a particular embodiment, the microprocessor detects that the ejector mechanism closure, aperture plate seal, etc. are in place and shuts down the device.

[0093] Several features of the device allow accurate dosing of a particular droplet size. The droplet size is set by the diameter of the holes in the mesh formed with high precision. As an example, the hole size of the aperture plate can range from 1 μm to 6 μm, 2 μm to 5 μm, 3 μm to 5 μm, 3 μm to 4 μm, and the like. Ejection rate, droplets per second are largely fixed by the frequency of aperture plate vibration, eg 108 kHz, operated by a microprocessor. In certain embodiments, there is a delay of less than 50 milliseconds between the detection of inhalation initiation and the formation of complete droplets.

[0094] Another aspect of the apparatus of the present disclosure that allows accurate dosing of a particular droplet size comprises the generation of droplets within the breathable range early in the inhalation cycle, thereby the mouth at the end of inhalation. Or minimize the amount of drug products deposited in the upper respiratory tract. In addition, the drug ampoule design allows the surface of the aperture plate to be wetted and ready to drain without user intervention, eliminating the need for shaking and priming. In addition, the vent structure of the drug ampoule and the design of the ejector mechanism closure system limit the evaporation of liquid from the reservoir from 150 μL to less than 350 μL per month.

[0095] The device can be constructed from the materials currently used in FDA approved devices. Extracts can be minimized by adopting standard manufacturing methods.

[0096] Any suitable material may be used to form the housing of the droplet delivery device. In certain embodiments, the material should be selected so that it does not interact with the components of the device or the ejected fluid (eg, drug solution or drug component). Polymer materials suitable for use in pharmaceutical applications can be used, including, for example, gamma-compatible polymer materials such as polystyrene, polysulfone, polyurethane, phenol, polycarbonate, polyimide, aromatic polyesters (PET, PETG).

[0097] Small volume drug ampoules can be constructed from any material suitable for the intended pharmaceutical use. In particular, the chemical contact portion may be made of a material compatible with the desired activator. As an example, in certain embodiments, the drug solution only contacts the inside of the drug solution storage and the inner surface of the aperture plate and the piezoelectric element. The wire connecting the piezoelectric ejector mechanism to the battery included in the base unit may be embedded in the drug ampoule shell to avoid contact with the drug solution. The piezoelectric ejector can be attached to the drug solution storage by a flexible bushing. If the bushing has the potential to come into contact with a chemical fluid, any suitable material known in the art can be used for purposes such as those used in piezoelectric nebulizers.

[0098] Using any suitable material known in the art for use in connection with pharmaceutical applications as the flexible membrane in the ampoule, the flexible membrane is a chemical fluid or background pressure fluid. Can be prevented from interacting with (eg, non-reactive polymeric materials). In certain embodiments, the flexible membrane is a flexible polymeric material that, when the chemical fluid is discharged so as to avoid creating a negative pressure on the chemical volume during use, is directed towards the surface of the ejector mechanism during use. Move in the direction. In certain embodiments, the flexible film comprises pleats or other directional etching to concentrate the pressure over the area above the ejector mechanism, thereby ejecting, as described below. Promotes an increase in the mass load of the chemical fluid on the instrument mechanism.

[0099] Any suitable background pressure fluid known in the art for use in connection with pharmaceutical applications, including but not limited to saline, distilled water, PBS solution, etc. A fluid can be selected. In certain embodiments, it is preferred to select a background pressure fluid similar to or with the same density as the therapeutic fluid so that the mass load of the background pressure fluid is substantially consistent with that of the therapeutic fluid. Although not intended to be a theoretical limitation, the background pressure volume of the fluid helps to provide a sufficient mass load of the chemical fluid on the surface of the ejector mechanism. In this regard, inadequate mass loading can result in inefficient wetting of the ejector surface and inefficient drainage of the chemical fluid.

[00100] In certain embodiments, the device mouthpiece may be removable, replaceable and washable. Similarly, the device housing and ampoules can be cleaned by wiping with a damp cloth. In certain embodiments, the mouthpiece may be joined to the housing (and optionally removable and / or replaceable), integrated into the housing, or part of the housing. In other embodiments, the mouthpiece may be joined to the drug solution delivery ampoule (and optionally removable and / or replaceable), integrated into the drug solution delivery ampoule, or part of the drug solution delivery ampoule.

[00101] Again, any suitable material can be used to form the mouthpiece of the droplet delivery device. In certain embodiments, the material should be selected so that it does not interact negatively with the components of the device or the released fluid (eg, drug solution or drug component). Polymeric materials suitable for use in pharmaceutical applications can be used, including, for example, gamma-compatible polymer materials such as polystyrene, polysulfone, polyurethane, phenol, polycarbonate, polyimide, aromatic polyesters (PET, PETG) and the like. .. The mouthpiece can be removable, replaceable, and sterilizable. This function provides a mechanism to minimize the accumulation of aerosolized drugs in the mouthpiece and improves the hygiene of drug delivery by facilitating replacement, disinfection, and irrigation. In one embodiment, the mouthpiece tube may be formed from a sterilizable, transparent polymer composition such as polycarbonate, polyethylene or polypropylene, as described herein.

[00102] In certain aspects of the disclosure, one or more of the housings, such as the inner surface of the housing along the airflow path, such as a mouthpiece, to reduce the buildup of droplets emitted due to the accumulation of static electricity during use. An electrostatic coating can be applied to the area. Alternatively, one or more parts of the housing may be formed from a charge dissipative polymer. For example, conductive fillers are commercially available and medical such as conductive fillers such as PEEK, polycarbonate, polyolefin (polypropylene or polyethylene), or styrene such as polystyrene or acrylic-butadiene-styrene (ABS) copolymers. It may be blended with a common polymer used in the application. Alternatively, in certain embodiments, one or more parts of the housing, such as the inner surface of the housing along the airflow path, such as a mouthpiece, may be coated with an antibacterial coating or a hydrophobic coating in use. Accumulation of discharged droplets can be reduced. Any suitable coating known for that purpose, such as polytetrafluoroethylene (Teflon®), can be used.

[00103] Any suitable differential pressure sensor with appropriate sensitivity, such as ± 5SLM, 10SLM, 20SLM, can be used to measure the pressure change obtained during a standard inhalation cycle. For example, Sensorion pressure sensors, SDP31 or SDP32 (US 7,490,511 B2), are particularly suitable for these applications.

[00104] In certain embodiments, the microprocessor in the device provides the exact timing and operation of the ejector mechanism based on the desired parameters, such as the duration of piezoelectric operation to achieve the desired dosage. Can be programmed to guarantee. In certain embodiments, the device contains memory (device, smartphone, app, computer, etc.) or interacts with memory during dose inhalation to facilitate the date and time of each eruption event and user monitoring. Record the user's inhalation flow and monitoring the usage of the chemical ampoule. For example, a microprocessor and memory can monitor the dose administered and the dose remaining in a particular drug ampoule. In certain embodiments, the drug solution ampoule may include components that include identifiable information, and the base unit may be the unique electrical resistance of the individual ampoule, RFID chip, or other readable microchip (authenticated microchip). It may include components for "reading" identifiable information based on (such as a chip) to detect that a drug ampoule has been inserted into the base unit. Dosage counts and lockouts may be pre-programmed into the microprocessor.

[00105] In certain embodiments of the present disclosure, the signal generated by the pressure sensor provides a trigger for activation and activation of the ejector mechanism, thereby during the peak period of the patient's inhalation (inspiratory) cycle. Or generate droplets and delivery droplets during peak periods. It ensures optimal deposition of the plume of droplets and delivery of the drug to the user's lung airways.

[00106] According to a particular aspect of the present disclosure, an in-line droplet delivery device with a small volume drug solution ampoule provides a reliable monitoring system that can date and time stamp the actual delivery of the drug solution. , For example, benefit patients through self-monitoring or involvement of caregivers and families.

[00107] As described in more detail herein, an in-line droplet delivery device with a small volume drug ampoule of the present disclosure detects inspiratory airflow and into memory (device, smartphone, app, computer, etc.). Inspiratory flow can be recorded / stored. A preset threshold (eg, 8-10 slm) initiates delivery of the drug over a predetermined period (eg, 1-1.5 seconds). The inspiratory flow is frequently sampled until the flow stops. The number of times delivery has been initiated is incorporated and displayed on the dosing counter LED of the device. The Bluetooth® feature enables wireless transmission of data.

[00108] Bluetooth® communication of the device may communicate the date, time, and number of operations per session to the user's smartphone. Software programming may provide charts, graphics, medication reminders, and alerts to patients and those who have been granted permission to the data. The software application may incorporate multiple drugs (eg, salbutamol, inhaled steroids, etc.) that use the devices of the present disclosure.

[00109] The device of the present disclosure is configured to dispense droplets during the correct portion of the inhalation cycle, eg, to hold the breath for the correct time after inhalation, for example to assist the patient with the use of the appropriate device. It may include instructional and / or instructional functions by instructing. The device of the present disclosure can monitor the air flow during inhalation, detect the end of inhalation (based on the measured flow rate), and signal the patient to hold breath for a period of time after the end of inhalation. It has an internal sensor / control that can allow this dual function.

[00110] In one exemplary embodiment, the patient breathes with an LED that turns on at the end of inhalation and turns off after a defined period of time (ie, the desired period of breath holding), for example 10 seconds. You may be instructed to stop. Alternatively, the LED may blink after inhalation and continue to blink until the end of the breath-holding period. In this case, the process in the device detects the end of inhalation, turns on the LED (or causes the LED to blink, etc.), waits for a defined period of time, and then turns off the LED. Similarly, the device inhales voice instructions, such as one or more burst sounds (eg, a 50 ms pulse at 1000 Hz), breath-holding voice instructions, voice countdowns, music, songs, melodies, and so on. It can also be emitted at the end to signal the patient to hold the patient's breath during the voice signal. If desired, the device may vibrate during or at the end of respiratory arrest.

[00111] In certain embodiments, the device uses the audio and visual methods (or sound, light and vibration) described above to notify the user when the breath-holding period begins and when the breath-holding period ends. Provides a combination of. Or show progress while holding your breath (such as a visual or audio countdown).

[00112] In other aspects, the devices of the present disclosure may provide guidance such as longer and deeper inhalation. The average peak inspiratory flow during inhalation (or dosing) may be utilized to provide guidance. For example, a patient may hear deeper breathing commands until 90% of the average peak inspiratory flow measured during inspiration (medication) stored in the device, telephone, or cloud is reached.

[00113] In addition, an image capture device including a camera, scanner, or other sensor, such as, but not limited to, a charge coupling element (CCD), is provided to detect and measure the emitted aerosol plume. May be done. All of these detectors, LEDs, Delta P-Transducers, and CCD devices provide control signals to the device's microprocessor or controller via, for example, Bloodooth® to monitor and detect droplet ejection. Used for measurement and control, as well as for reporting patient compliance, treatment time, dosage, and usage history.

[00114] The drawings are referred to herein, and similar components are exemplified by similar reference numbers.
[00115] Figures 1A and 1B show an in-line droplet delivery device with an exemplary small volume drug ampoule of the present disclosure. FIG. 1A shows an in-line droplet delivery device 100 having a mouthpiece cover 102 in a closed position, and FIG. 1B shows an in-line droplet delivery device 100 having a mouthpiece cover 102 in an open position. As shown, the droplet delivery device is configured in an in-line orientation, the housing, its internal components, and various device components (eg, mouthpiece, air inlet flow element) to provide a knife handheld device. Etc.) are oriented substantially in-line or in parallel configuration (eg, along the air flow path).

[00116] As shown in FIGS. 1A and 1B, the in-line droplet delivery device 100 includes a base unit 104 and a small volume drug delivery ampoule 106. As shown in this embodiment and discussed in more detail herein, the small volume drug delivery ampoule 106 slides to the front of the base unit. In certain embodiments, the mouthpiece cover 102 may include a push element 102a that facilitates insertion of the drug solution delivery ampoule 106. Also, one or more airflow inlets or openings 110 are shown. As an example, there may be air inlets on the opposite side of the device, multiple air inlets on the same side of the device, or a combination thereof (not shown). In addition, the in-line droplet delivery device 100 includes a mouthpiece 108 on the airflow outlet side of the device.

[00117] With reference to FIG. 2, exploded views of the exemplary in-line drop delivery device of FIGS. 1A and 1B are shown, the power / actuation button 201, the electronic circuit board 202, the ejector mechanism and A small volume drug delivery ampoule 106 with a storage (not shown, further described herein), a power supply 203 with associated contacts 203a (eg, three optionally rechargeable AAA batteries), and Includes the internal components of the housing, including. In certain embodiments, the reservoir can be a disposable ampoule that can be replaceable, disposable, or reusable. Also shown are one or more pressure sensors 204 and any spray sensor 205. In certain embodiments, the device may include various electrical contacts 210 and 211 to facilitate the operation of the device when inserting the drug solution delivery ampoule 106 into the base unit. Similarly, in certain embodiments, the device may include a slide 212, a post 213, a spring 214, and an ampoule lock 215 to facilitate insertion of the drug solution delivery ampoule 106 into the base unit.

[00118] The components can be packaged within the housing and generally oriented in an in-line configuration. The housing can be disposable or reusable, single dose or multiple doses. Various configurations for forming the housing are within the scope of the present disclosure, but as shown in FIG. 2, the housing may include a top cover 206, a bottom cover 207, and an inner housing 208. The housing may also include a power housing or cover 209.

[00119] In certain embodiments, the device may include audio and / or visual display, for example, to provide instructions and communications to the user. In such embodiments, the device may include a speaker or audio chip (not shown), one or more LED lights 216, and an LCD display 217 (interfaces with an LCD control board 218 and a lens cover 219). The housing may be handheld, for example via a Bluetooth® communication module or similar wireless communication module for communication with the subject's smartphone, tablet, or smart device (not shown). It may be configured to communicate with other devices.

[00120] In certain embodiments, the air inlet flow elements (not shown, see, eg, FIGS. 5A-5C and 11A-18D) are placed in the airflow at the air inlet of the housing and of the aperture plate. Promoting non-turbulent (ie, laminar and / or transitional) airflow across the outlet side, providing sufficient airflow, and ejected droplet flow through the droplet delivery device during use. Can be configured to guarantee. In some embodiments, the air inlet flow element may be located within the mouthpiece. Aspects of this embodiment further arrange laminar flow elements with different sized openings and different configurations to selectively increase or decrease internal pressure resistance, as described in more detail herein. This makes it possible to customize the internal pressure resistance of the particle delivery device.

[00121] As a non-limiting example, an exemplary method of inserting and using an ampoule and turning off the device can be performed as follows.

1. 1. First, insert a new ampoule and push it into the slide guide of the device, the door of the device opens, and the ampoule slides into the ampoule position 1. In this setting, the ampoule's aperture plate seal or cover is open and the device contacts the ampoule's electrical contacts. The system turns on and is ready for breathing. When the device door opens, a beep sounds and the LED indicator flashes green or flashes to notify the user that the system is on and ready for inhalation through the mouthpiece.

2. 2. When the patient inhales, a preset pressure value is reached, detected by a pressure sensor located inside the housing (such as the Delta P sensor), and a second audio or LED indicator indicates that medication has begun. Is done. After the dosing has been initiated and delivered, another audio and / or LED indicator may be activated until the end of the spray cycle time, eg, 1-5 seconds (or other defined dosing time). In addition, if desired, when the medication is delivered, the medication counter displayed on the LCD indicates that the medication has been delivered by reducing the number of medications displayed on the LCD.

3. 3. The audio and / or LED indicator is activated to warn the user that the device is about to power off if no further medication is required, for example after 15 seconds, and then the device , Low power, can go to sleep mode.

4. If no further medication is required, close the device door, push the ampoule to the unused position, close the aperture plate seal or cover, and put the device into sleep mode. In addition, the system is turned off when the slide mechanism releases pressure from the on / off switch.

5. When the patient is ready to apply additional medication, the device door opens and the ampoule slides towards the mouthpiece. The spring-loaded climate pushes the mouthpiece from the unused position to the used position, which opens the aperture plate seal or cover.

[00122] More specifically, specific exemplary embodiments of the mode of insertion of the drug solution ampoule and the operation of the apparatus are shown in FIGS. 3A-1 to 3C-3. With reference to FIGS. 3A-1 and 3A-2, when the small volume chemical ampoule (1) is first inserted and pushed into the device slide guide (1a), the device door (2) opens and the ampoule slides to the ampoule. It snaps into position 1. The oval button (ampoule lock) (1b) clicks back and locks the ampoule in place. In this setting, the seal on the aperture plate is open, the device and the four electrical contacts on the ampoule are in contact, the system is turned on, and it is ready to activate breathing. The two contacts (3) on the front complete the circuit that operates the piezoelectric element. On the other hand, the two contacts (4) on the back are used to provide specific information about the ampoule, such as ampoule ID, drug type, dosage, etc.

[00123] Ampoule position 1 (A) is shown with reference to FIGS. 3B-1 and 3B-2. An oval button (1b) secures the ampoule in place and connects the four electrical contacts, the front (3) and the back (4), to complete the electrical circuit. When the ampoule is in position 1, the electronic component that activates the on / off button (1c) is pushed by the spring-loaded slide mechanism (5). FIG. 3B-1 provides a bottom view of the spring-loaded slide mechanism (5) and the on / off button (1c) in on mode. FIG. 3B-2 shows an exploded view (5a) of the side brackets of the spring-loaded slide (5) and their positions (5a-arrows) through the slot (5b) of the device, with the device door open. Occasionally, when the ampoule (5c) is touched to push the ampoule forward and the on / OFF button (1d) is touched, the on / OFF switch (1c) is activated. The device on / off button (1c) is activated by the slide (5) when the mouthpiece cover (2) is closed, pushing the ampoule back to position 2. Here, when the aperture plate seal is in the closed position and the pressure of the on / OFF switch is released, the power to the device is turned off.

[00124] With reference to FIGS. 3C-1, 3C-2, and 3C-3, a cross-sectional view of the device into which a small capacity ampoule (internal function not shown) is inserted is shown with the ampoule sliding mechanism and on. The position of the / OFF switch is better shown. FIG. 3C-1 shows ampoule position 1 in which the mouthpiece cover is in the open position and the on / OFF switch is in the on position. FIG. 3C-2 shows the ampoule position 2 in which the mouthpiece cover is in the closed position and the on / OFF switch is in the off position. FIG. 3C-3 shows ampoule position 2 with the mouthpiece cover in the open position and the on / off switch in the off position.

[00125] However, it should be noted that the devices and methods of the present disclosure are not so limited and various modifications and extensions of the manner of operation are assumed to be within the scope of the present disclosure.

[00126] For example, small volume drug ampoules can be used in simple "snap-on" or "clip-in" configurations that automatically activate the device. In certain embodiments, in a small volume ampoule configuration, the seal or cover of the aperture plate may be, for example, because the environment of a small volume ampoule does not require long-term use and storage of the fluid reservoir in the device. It may not be necessary in all embodiments to maintain sterility and / or to minimize evaporation of the therapeutic fluid. Further, in certain embodiments, the device can be configured, for example, through on-board software, to allow the user to breathe multiple times to ensure that the full volume of the therapeutic agent is ejected (eg, of respiratory activation). Counting, monitoring of ejected droplets, etc.). In such embodiments, the device may be configured to ensure that administration accuracy is maintained.

[00127] In another embodiment, FIGS. 4A and 4B show an in-line droplet delivery device with an alternative small volume drug ampoule of the present disclosure, FIG. 4A shows a mouthpiece cover 402 in a closed position. Shown is an in-line droplet delivery device 400 with a base unit 404 with, FIG. 4B shows a drop delivery device 400 with a base unit 404 with a mouthpiece cover 402 in the open position. As shown, the droplet delivery device is configured in in-line orientation, with the housing, its internal components, and various device components (eg, mouthpiece, air inlet flow element, etc.) forming a small handheld device. They are oriented substantially in-line or in parallel (eg, along the air flow path) so that they do.

[00128] In the embodiment shown in FIGS. 4A and 4B, the in-line droplet delivery device 400 includes a base unit 404 and a small volume drug delivery ampoule 406. The small volume drug delivery ampoule 406 slides in front of the base unit, as shown in this embodiment and described in more detail herein. In certain embodiments, the mouthpiece cover 402 may include an aperture plate plug 412. Also shown is one or more air inlets or openings 410 in the mouthpiece 408. As an example, there may be multiple air inlets on the opposite side of the device, multiple air inlets on the same side of the device, or a combination thereof (not shown). Good. In addition, the in-line droplet delivery device 400 includes a mouthpiece 408 on the airflow outlet side of the device.

[00129] An exploded view of the exemplary in-line droplet delivery device of FIGS. 4A and 4B is shown with reference to FIG. 5, with electronic circuit board 502 and optional vents 431 and steam barrier 432. A chemical delivery amplifier 406 with a top cover 430, an ejector mechanism 434, a small volume chemical storage (internal function not shown) 435, electrical contacts 436, and one or more sensor ports 437, and a power supply 503 (eg, eg). It shows the internal components of the housing, including three AAA batteries) that can be optionally recharged. In certain embodiments, the device may also include various electrical contacts 442 and sensor ports 444 to facilitate device activation by inserting the drug solution delivery ampoule 406 into the base unit 404. Similarly, in certain embodiments, the device may include a resistor or chip 504 to facilitate insertion and detection of the drug solution delivery ampoule 406 into the base unit 404.

[00130] In certain embodiments, the reservoir can be a disposable reservoir that can be replaceable, disposable, or reusable. As shown in FIG. 5, in certain embodiments, the small volume drug delivery ampoule may also include or be joined with a mouthpiece 408 and a mouthpiece cover 402. As shown, the ejector mechanism 434 is along the mouthpiece 408 and the reservoir 435 so that the aperture plate is perpendicular to the direction of the airflow and the droplet flow is emitted parallel to the direction of the airflow. Can be placed. The mouthpiece cover 402 may further include an aperture plate plug 412.

[00131] The components may be packaged in a housing and generally oriented in an in-line configuration. The housing can be disposable or reusable, single dose or multiple doses. Although various configurations for forming the housing are within the scope of this disclosure. As shown in FIG. 5, the housing may include a top cover 506, a bottom cover 507, and an internal housing 508. The device may also include, for example, one or more ampoule removal buttons 550 located on the sides of the housing to facilitate removal of the drug solution delivery ampoule 406 when inserted into the base unit 404.

[00132] In certain embodiments, the device may include audio and / or visual display, for example, to provide instructions and communications to the user. In such embodiments, the device may include a speaker or audio chip 520, one or more LED lights 516, and an LCD display 517 (interfaced with an LCD control board 518 and a lens cover 519). The housing may be handheld, for example via a Bluetooth® communication module or similar wireless communication module for communication with the subject's smartphone, tablet, or smart device (not shown). It may be configured to communicate with other devices.

[00133] A cross-sectional view of the in-line device of FIGS. 4A and 4B is shown with reference to FIG. 6, with an exemplary configuration of the overall shape of the interior of the reservoir 435 and its ejector mechanism 434. Relationships (further internal functions not shown) are shown. As shown, the reservoir 435 is sized and shaped so that the volume of fluid held in the reservoir is poured and directed towards the discharge surface of the aperture plate during use. More specifically, as illustrated, the bottom surface of the drug solution storage can be tilted towards the ejector mechanism to facilitate the flow of fluid within the storage during use. Without the intention of limiting by theory, such a configuration may be particularly suitable for orienting a device in which the ejector mechanism is oriented perpendicular to the direction of airflow. However, it should be noted that this disclosure is not so limited and that various shapes, sizes and configurations of ampoules are assumed to be within the scope of this disclosure.

[00134] FIG. 7 shows the base unit 404 of the embodiment of FIGS. 4A and 4B in which the drug solution delivery ampoule is not inserted. If no drug delivery ampoule is inserted, a track 40, electrical contacts 442, and sensor port 444 for guiding the ampoule into place are shown. Also, a removal button 450 is shown.

[00135] FIGS. 8A and 8B show a front view (FIG. 8A) and a rear view (FIG. 8B) of a small volume drug solution delivery ampoule 406 to which the mouthpiece cover 402 is attached and in a closed position. FIG. 8B shows the ampoule's electrical contacts 436 and sensor ports 437, as well as protruding slides 452 to facilitate placement of the ampoule on track 440 during insertion. As an example, when a small volume drug delivery ampoule 406 is inserted into the base unit 404, the protruding slide 452 is coupled to the track 440, the sensor port 437 is coupled to the sensor port 444, and the electrical contact 436 is coupled to the electrical contact 442. .. The small volume drug delivery ampoule is pushed by the base unit and fixed in place with the protruding slide and track engaged to each other. During use, a pressure sensor located on the control board senses a pressure change in the device via a pressure sensing port (such as in the mouthpiece). To facilitate detection of pressure changes, the base unit includes a second pressure sensing port and an external channel (not shown) to facilitate sensing of reference or ambient pressure.

[00136] FIG. 9 shows a cross section of an exemplary small volume chemical ampoule 406. As shown, the small volume chemical ampoule 406 includes a flexible membrane 920 that separates the reservoir into two volumes, a first background pressure fluid volume 925 and a second chemical fluid volume 930. The small ampoule may also include an air exchange vent (eg, a superhydrophobic filter) 935, and an optional filling port 940. Any suitable size and shape configuration of the reservoir can be used. As a non-limiting example, for a dose of 20 μL in a 5 mm ejector, the small volume ampoule can be sized and shaped to be a well with a diameter of 5 mm and a height of 1 mm.

[00137] As described herein, the drug solution storage and / or small volume drug solution ampoule may include various vents and / or vapor barriers to facilitate ventilation and the like. 10A-10C are configured to be unaffected by the pressure differences that may occur when the user moves from sea level to the sea and highlands, for example while traveling on an airplane where pressure differences greater than 4 psi can exist. An exemplary reservoir or ampoule is shown. As shown, FIG. 10A shows a perspective view of an exemplary ampoule 900. 10B and 10C show exploded views of the ampoule 900 viewed from above and below the perspective. With reference to FIGS. 10B and 10C, the ampoule 900 generally includes an upper cover 901 and a lower cover 902. The ample 900 may be configured to include one or more superhydrophobic filters 904 that cover the one or more vents 906, and the fluid reservoir housing is a vapor barrier 905 of a spiral channel (or similar shape). The vapor barrier 905 provides free exchange of air to and from the fluid reservoir while at the same time preventing moisture or fluid from entering the reservoir, thereby causing fluid leakage or aperture. Reduce or prevent deposition on the plate surface. If necessary, one or more O-rings 903 or similar sealing mechanisms are used to form a seal between the top cover 901 and the bottom cover 902 connected to the vapor barrier 905. Although not intended to be limiting, superhydrophobic filters and vents can generally allow ventilation and air pressure equilibration within the fluid reservoir while maintaining a sterile environment within the fluid reservoir. The vapor barrier of the spiral channel generally prevents the transfer of moisture to and from the fluid reservoir (eg, through the vents).

[00138] According to one aspect, the in-line droplet delivery device with the small volume drug solution ampoules of the present disclosure is placed in the air stream at the air inlet of the device and is non-turbulent (ie, across the outlet side of the aperture plate). Air configured to facilitate laminar and / or transitional airflow, provide sufficient airflow, and ensure that the ejected droplet flow flows through the droplet delivery device to the flow used. It may include inlet flow elements (see, eg, FIGS. 11A-11C and 13A-20D). In some embodiments, the air inlet flow element may be located within the mouthpiece. In addition, aspects of this embodiment selectively increase internal pressure resistance, allowing the placement of laminar flow elements with different sized openings and different configurations, as described in more detail herein. Alternatively, the internal pressure resistance of the droplet delivery device can be customized by reducing it.

[00139] According to a particular embodiment of an in-line droplet delivery device with a small volume drug solution amplifier of the present disclosure, the device is placed in the air flow at the air inlet of the device and is not across the outlet side of the aperture plate. To facilitate turbulent (ie, laminar and / or transitional) airflow and provide sufficient airflow to ensure that the ejected droplet flow flows through the droplet delivery device to the flow used. May include configured air inlet flow elements. In some embodiments, the air inlet flow element may be located within the mouthpiece. In addition, the air inlet flow element allows customization of the pressure resistance of the internal device by designing different sized openings and different configurations to selectively increase or decrease the internal pressure resistance.

[00140] As described in more detail herein, the air inlet flow element may be located behind the outlet side of the opening plate along the direction of the air flow, or along the direction of the air flow. It may be placed in-line or in front of the outlet side of the opening plate. In certain embodiments, the air inlet flow element comprises one or more openings that are formed through and configured to increase or decrease internal pressure resistance within the droplet delivery device during use. For example, an air inlet flow element comprises an array of one or more openings. In one embodiment, the air inlet flow element comprises one or more baffles, for example, one or more baffles include one or more air flow openings.

[00141] In certain embodiments, the air inlet flow element provides optimal airway resistance to achieve the peak inspiratory flow required for deep inspiration that facilitates delivery of droplets released deep into the pulmonary airways. Designed and configured as. The air inlet flow element also functions to facilitate laminar flow across the aerosol plume outlet port, contributing to air flow reproducibility and stability and ensuring optimal accuracy of the delivered dose.

[00142] Not intended to be limited by theory, but in accordance with aspects of the present disclosure, the size, number, and size of flow restrictors (eg, openings, holes, flow blocks, etc.) in the air inlet flow elements of the present disclosure. The shape and orientation can be configured to provide the desired pressure drop within the in-line droplet delivery device. In certain embodiments, it may generally be desired to provide a pressure drop that is not significant enough to strongly affect the user's breathing or respiratory perception.

[00143] In certain embodiments, different configuration, size, and shape flows to accommodate lung differences and inspiratory flow rates associated with young and old, small and large, and various lung disease states. The use of airflow elements with limits (eg, openings, holes, flow blocks, etc.) or the use of adjustable openings may be required. For example, if the aperture is adjustable by the patient (perhaps by having a rotatable throttling), read the aperture hole setting and lock its position to measure the size of the aperture hole, or flow rate. A method is provided to prevent unintended changes. Pressure detection is an accurate method of flow measurement, but other embodiments include, for example, a thermal wire or thermistor-type flow measurement method that loses heat in proportion to the flow, a blade (turbine flow meter technology), or a spring. A load plate may also be used and is not limited to these examples.

[00144] For example, FIGS. 11A-11C show specific exemplary air inlet flow elements of the present disclosure. 11A-11C also show the location of pressure sensors, mouthpieces, and air channels for reference pressure sensing. However, this disclosure is not so limited and other configurations, including those described herein, are considered to be within the scope of this disclosure. Although not so limited, the air inlet flow elements of FIGS. 11A-11C are particularly suitable for use with the in-line droplet delivery apparatus of FIGS. 1A, 1B.

[00145] More specifically, FIG. 11A includes a mouthpiece cover 1001, a mouthpiece 1002, and a small volume chemical ampoule 1003 including a storage unit (internal function not shown) 1004 and an ejector mechanism 1005. A partial cross section of an in-line droplet delivery device 1000 having a small volume chemical ampoule of the present disclosure is shown. As illustrated, the droplet delivery device includes an air inlet flow element 1006 having an array of holes 1006a at the air inlet of the mouthpiece 1002. A pressure sensor port 1007 that can be used to detect changes in pressure within the mouthpiece is also shown. A front view of the device 1000 is shown with reference to FIG. 11B, and a second pressure sensor port 1008 is shown to provide reference or ambient pressure sensing.

[00146] FIG. 11C shows a partially exploded view of the mouthpiece 1002 and the internal housing 1011. As shown, the mouthpiece 1002 includes an intake flow element 1006 having an array of holes 1006a and a pressure sensor port 1007. Further, the mouthpiece 1002 includes, for example, an ejection port 1114 located on the upper surface of the mouthpiece so as to be aligned with an ejector mechanism that allows the ejection of the droplet flow into the air flow of the device during use. Other sensor ports 1115 may be optionally positioned along the mouthpiece to allow for the desired sensor function, eg spray detection. The mouthpiece may also include a positioning baffle 1116 that joins the base unit upon insertion. The inner housing 1011 includes a pressure sensor board 1009 and an outer channel 1010 to facilitate the sensing of reference or ambient pressure. The internal housing includes a first pressure sensing port 1112 that facilitates sensing of pressure changes within the device (eg, in the mouthpiece or housing) and a second pressure sensing port 1113 that facilitates sensing reference or ambient pressure. And further include.

[00147] In this regard, FIG. 12A is an exemplary air inlet flow element similar to that of FIGS. 11A-11C as a function of the number of holes (29 holes, 23 holes, 17 holes). The relationship between the differential pressure passing through and the flow rate is shown. With reference to FIG. 12B, when the flow rate is plotted as a function of the square root of the differential pressure, the flow rate to the differential pressure as a function of the hole size is shown to have a linear relationship. The number of holes is kept constant at 17 holes. These data provide a way to select the design of the air inlet flow element to provide the desired withstand voltage, as well as model the relationship between flow rate and differential pressure as measured by an exemplary droplet delivery device. provide.

[00148] Specific non-limiting exemplary air inlet flow elements may be 29 holes, each 1.9 mm in diameter. However, the present disclosure is not limited to these examples. For example, the air inlet flow element has, for example, a diameter of 0.1 mm to a cross-sectional diameter of the air inlet tube (eg, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4. It can have a hole diameter in the range up to a diameter equal to 5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, etc.), and the number of holes is from 1 to the number of holes to achieve the desired airflow limit. For example, it may be in the range of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 29, 30, 60, 90, 100, 150 and the like.

[00149] FIGS. 13A-20D show alternative embodiments of the air inlet flow elements of the present disclosure. Also, FIGS. 13A-20D show exemplary arrangement of air inlet flow elements in the airflow of the device within the mouthpiece, as well as joining of the mouthpiece containing the air inlet flow elements to a drug solution delivery ampoule.

[00150] FIG. 13A shows an exemplary drug solution delivery ampoule with a mouthpiece joined on the air outlet side of the device. The mouthpiece includes two air inlets on the sides, but without an internal air inlet flow element that provides resistance to airflow. FIG. 13B shows a front cross section, FIG. 13C shows a side cross section, and FIG. 13D shows the same view with exemplary dimensions. FIG. 14A and 15A to the drug solution delivery ampoule show a similarly constructed mouthpiece having two air inlets on the sides but no internal air inlet flow element that provides resistance to air flow. 14B and 15B also show a front cross section, FIGS. 14C and 15C show side cross sections, and FIGS. 14D and 15D show the same view with exemplary dimensions to show differences in configuration between embodiments. ing. For example, the embodiment of FIG. 13 has an opening of 6.6 mm in length and 2 mm in height, and the embodiment of FIG. 14 has an opening of 7.9 mm in length and 2.5 mm in height. However, the embodiment of FIG. 15 has an opening having a length of 8.1 mm and a height of 3 mm. Of course, the present disclosure is not limited to these particular dimensions, and it is assumed that various dimensions and the number of air inflow openings are within the scope of the present disclosure.

[00151] FIG. 16A shows an exemplary drug solution delivery ampoule with a mouthpiece joined on the air outlet side of the device. The mouthpiece includes two air inlets on the outside of the mouthpiece and two internal baffles with additional air inlets that provide airflow resistance and modeling. FIG. 16B shows a front cross section, 16C shows a side cross section, and FIG. 16D shows the same view with exemplary dimensions. FIG. 17A shows a similarly constructed mouthpiece that includes two air inlets on the outside of the mouthpiece and two internal baffles with additional air inlets that provide airflow resistance and modeling. However, the internal baffle (height 10 mm) of FIG. 17A is larger than that of FIG. 16A (height 5 mm). FIG. 17B shows a front cross section, FIG. 16C shows a side cross section, and FIG. 16D shows the same view with exemplary dimensions.

[00152] FIG. 18A shows an exemplary drug solution delivery ampoule with a mouthpiece joined on the air outlet side of the device. The mouthpiece has two air inlets on the outside of the mouthpiece and two additional air inlets, which are substantially concentric baffles (top and bottom of the mouthpiece) to provide airflow limitation and modeling. Includes two arcs) that form a circle with. FIG. 18B shows a front cross section, FIG. 18C shows a side cross section, and FIG. 18D shows the same view with exemplary dimensions. FIG. 19A shows a similarly constructed mouthpiece with substantially concentric internal baffles, the internal baffle containing four air inlets to provide resistance and modeling of airflow. FIG. 19B shows a front sectional view, 19C shows a side sectional view, and FIG. 19D shows the same view with exemplary dimensions.

[00153] FIG. 20A shows an exemplary drug solution delivery ampoule with a mouthpiece joined on the air outlet side of the device. The mouthpiece includes two air inlets on the outside of the mouthpiece and a substantially concentric baffle having two additional air inlets to provide airflow resistance and modeling. In addition, the internal region of the mouthpiece between the concentric baffles and the wall of the mouthpiece contains array elements located above the air inlet, providing additional resistance and modeling to the air flow. The array elements are arranged parallel to the direction of the air flow. 20B shows a front sectional view, 19C shows a side sectional view, and FIG. 20D shows the same view with exemplary dimensions.

[00154] According to the present disclosure, the presence of an internal air inlet flow element has been found to substantially improve the spray efficiency of exemplary fluid solutions (deionized water and albuterol solutions). For example, as shown in FIG. 21 at 30 SLM, the spray efficiency is improved from 47% to 66% by the inner air inlet flow element, and when the internal air inlet is placed away from the ejection flow, the spray efficiency is 80% or more. Improve to. The mouthpiece and chemical reservoir are a single unit for weighing and delivering from the mouthpiece to the user before eruption (W1), after eruption (W2), and after drying the mouthpiece (W3). The proportion of the excreted drug solution can be measured. Spray efficiency = (W1-W2) / (W1-W3)

[00155] In certain aspects of the disclosure, an in-line device with a small volume chemical ampoule optionally protects the surface of the aperture plate, minimizes evaporation loss, and when the device is closed and not in use. It can be configured to minimize pollution. However, as mentioned above, the environment of small volume chemical ampoules does not require long-term use and storage of the fluid reservoir in the device, so in certain embodiments, the small volume ampoule configuration will seal the aperture plate or Covers may not be needed in all embodiments, for example, to maintain sterility and / or minimize evaporation of the therapeutic fluid.

[00156] For example, as described herein, the surface of the aperture plate of the ejector mechanism can be closed / sealed to the housing or mouthpiece cover when the reservoir / ampoule is in the closed position. However, in certain embodiments, if the reservoir / ampoule includes an O-ring or gasket to facilitate sealing of the surface of the aperture plate of the ejector mechanism, the reservoir / ampoule between the open and closed positions. In certain embodiments, the slide creates friction that must be overcome by the compression springs when opening and closing.

[00157] In one embodiment, the friction between the ampoule's O-ring and the device housing is reduced by applying a compressive force between the ampoule and the device housing in the last few millimeters when the ampoule is closed. be able to. This limits the high friction of the first few millimeters while the compression spring provides maximum force, and the high friction of the last few millimeters when the ampoule closes almost, and the door resistance is applied by the user. It will be easy. The force applied when the door is nearly closed minimizes the reaction force at the door hinges and improves the robustness of the device. Since pressure is applied to the O-ring over a short distance, wear on the O-ring (or gasket) is also reduced.

[00158] In certain embodiments, applying a compressive sealing force during the last few millimeters of operation of the ampoule to the closed position is the opposite surface (ampoule) as the ampoule approaches the closed position. This can be achieved by utilizing a ramp on either the ampoule side or the device side of the ampoule track that engages with the device to, or the ampoule to the device. It can also be a pair of tilts that operate as the ampoule approaches the closed position. In certain embodiments, the point of contact between the ampoule and the device is preferably aligned with the center of pressure on the O-ring, creating a uniform sealing pressure. Note that the total vertical movement generated by the ramps only needs to be within the range of 0.1 mm in order to achieve sufficient compression for good sealing.

[00159] Instead of the sealing force generated by the ampoule's fixed movement towards the device, a flexible compression element may exert a downward force that rises as the ampoule approaches the closed position. As a non-limiting example, this can be a slope that intersects a flexible rubber-like material or metal or plastic spring, including a cantilever (leaf) spring that the slope encounters when it reaches the closed position of the ampoule. ..

[00160] The compressive force applied to the O-ring need not be large, but is sufficient for the compliant O-ring to seal against the surface roughness of the device surface. In certain embodiments, the more flexible material will require less compressive force to seal. Similarly, O-rings can be made from slippery materials such as Teflon-coated or Teflon-encapsulated materials to reduce the slip friction of ampoules. Similarly, sealing can be done by surface lip sealing.

[00161] FIGS. 22A-22C show exemplary embodiments showing an ampoule lip tilt structure that pushes down the ampoule to compress the O-ring when in the "closed" position. Note that the size of the slope is very exaggerated, as shown. In one embodiment, the ramp can be about 0.1 to 0.2 mm high. FIG. 22A shows an end view showing an ampoule with a lip engaged to a track that is part of the body of the device. FIG. 22B shows how the ampoule moves from the closed position to the open position. The mouthpiece and user are on the right. FIG. 22C shows a side view of an ampoule on a track having a slope on the lip to apply force to the aperture plate seal, showing the closed and open positions.

[00162] In other embodiments, the surface of the aperture plate may be protected by a mouthpiece cover. For example, as shown in FIG. 22D, the mouthpiece cover 2100 has an aperture plate plug 2102 of a particular size and shape to form a binding seal against the surface of the aperture plate 2104 when the cover is closed. Can include. In certain embodiments, the aperture plate plug 2102 has a stepped shape such that the plug forms a seal against the surface of the housing around the aperture plate without exerting direct pressure on the surface of the aperture plate. obtain.

[00163] In certain embodiments, as shown herein, the reservoir / cartridge module is provided by a housing electronics that includes key parameters such as ejector mechanism function, drug solution identification, and information about patient dosing intervals. It may include components that can possess the information to be read. Some information is added to the module at the factory and some is added at the pharmacy. In certain embodiments, the information placed by the factory may be protected from changes by the pharmacy. The module information may be carried as a printed barcode or a physical barcode encoded in the module geometry (such as a light transmitting hole in the flange read by a sensor in the housing). Information may also be possessed by programmable or non-programmable microchips on modules that communicate with electronic devices in the housing.

[00164] As an example, modular programming in a factory or pharmacy may include a drug solution code that can be read by the device, communicated to the relevant user's smartphone via Bluetooth®, and verified as correct for the user. .. If the user inserts a module such as an incorrect, generic, or damaged module into the device, the smartphone may prompt the device to lock out the operation. This can provide a user safety and security method not possible with a passive inhaler. In other embodiments, the device's electronics are restricted in use for a limited period of time (perhaps a day, or weeks, or months), aging or contamination of the drug or accumulation of particles in the device housing. Can avoid problems with.

[00165] In-line drop delivery devices are used to facilitate device activation, spray verification, patient compliance, diagnostic mechanisms, or for data storage, big data analysis, as described herein. Various sensors and detectors can be further included as part of a large network of, and for devices used for the care and treatment of interacting and interconnected subjects. In addition, the housing may include an LED assembly on its surface to indicate various status notifications such as on / ready, error.

[00166] The air outlet of the housing of the droplet delivery device, which exits as the plume of the ejected droplets is sucked into the airway of interest, is circular, oval, rectangular, hexagonal, or, but not limited. It can have other shapes, and the length of the tube can also have a straight, curved, or ventilated shape, but not limited to.

[00167] In another embodiment (not shown), a mini fan or centrifugal blower may be located on the air inlet side of the laminar flow element or inside the housing 116 in the airflow. Minifans can generally provide additional airflow and pressure to the plume output. For patients with low lung output, this additional plume can ensure that the exhalation of droplets is pushed through the device into the subject's airways. In certain embodiments, this additional airflow source ensures that the droplets are cleaned cleanly from the plume outlet port and provides a mechanism for spreading the droplet plume into the airflow to increase the separation between the particles. The airflow provided by the minifan also acts as a carrier gas, ensuring proper drug dilution and delivery.

[00168] In other embodiments, the internal pressure resistance of the in-line droplet delivery device is customized to individual users or groups of users by modifying the design of the mouthpiece tube, including various configurations of air vent grids or openings. And the resistance of the air flow through the device when inhaled by the user increases or decreases. For example, different sizes and numbers of air inlets may be used to achieve different resistance values, thereby achieving different internal device pressure values. This feature can provide a mechanism for easily and quickly adapting and customizing the airway resistance of a particle delivery device to the health or condition of an individual patient.

[00169] In another aspect of the present disclosure, in certain embodiments, the in-line droplet delivery device provides a variety of automation, monitoring, and diagnostic functions. As an example, as described above, device activation may be provided by automatic subject breathing activation. In addition, in certain embodiments, the device may provide automatic spray verification to ensure that the device produces the appropriate particle production and is provided for the appropriate dosing to the subject. In this regard, the particle delivery device may include one or more sensors to facilitate such functionality.

[00170] For example, an airflow sensor located on the mouthpiece may measure the flow rates of inspiration and exhalation flowing inside and outside the mouthpiece. The sensor is placed so that it does not interfere with drug delivery or serve as a reservoir of residue, bacterial growth, or promotion of contamination. A differential pressure (or gauge pressure) sensor downstream of a flow limiter (eg, an air inlet flow element) measures airflow based on the pressure difference between the internal and external air pressure of the mouthpiece. During inhalation (inspiratory flow), the pressure of the mouthpiece is lower than the ambient pressure, and during exhalation (exhalation), the pressure of the mouthpiece is higher than the ambient pressure. The magnitude of the pressure difference during the inspiratory cycle is a measure of the magnitude of airflow and airway resistance at the end of the air inlet of the delivery tube.

[00171] Also, a Bluetooth® communication module or a similar wireless communication module may be provided to link the droplet delivery device to a smartphone or other similar smart device (not shown). The Bluetooth® connection facilitates the implementation of various software or applications that can provide and facilitate patient discipline regarding the use of the device. A major obstacle to effective inhalation therapy was the patient's resistance to prescribed aerosol therapy or an error in the use of the inhaler device. By displaying the patient's inspiratory cycle (flow vs. time) and total volume plot in real time on the smartphone screen, the patient has a predetermined total inspiratory volume target recorded on the smartphone during the training process in the doctor's office. Will challenge to reach. The Bluetooth Connection is defined by providing a means of storing and achieving compliance information and diagnostic data (on large data storage networks such as smartphones and the cloud) that may be used to care for patients. Facilitates active participation of patients in drug therapy and promotes medication compliance.

[00172] More specifically, in certain embodiments, the droplet delivery device may provide automatic spray verification via LEDs and a photodetector mechanism. For example, an infrared transmitter (eg, IR LED, or UV LED below 280 nm) 126, which can detect the plume of droplets and thereby be used for detection and verification of spray, and infrared or UV (cut below 280 nm). A UV) photodetector with off may be mounted along the droplet ejection side of the device. The IR or UV signal can be used to interact with the aerosol plume to confirm that the plume of the droplet has been released, as well as to provide a measure of the dosage of the corresponding released drug. Examples include, but are not limited to, infrared 850 nm emitters (MTE2087 series) or GaN photodetectors with narrow viewing angles of 8, 10, and 12 degrees for aerosol plume verification in the solar blind region of the spectrum. 275 nm UV LED can be mentioned. Alternatively, depending on the application, an LED of 280 nm or less (for example, an LED of 260 nm) may be used for disinfecting the spacer tube.

[00173] As an example, the concentration of the drug in the released stream can be made according to Beer's law equation (absorbance = eLc). Where e is the molar extinction coefficient (or molar extinction coefficient) and is a constant associated with a particular compound or formulation, and L is the path length or distance between the LED emitter and the photodetector. Yes, c is the concentration of the solution. This embodiment provides a measure of drug concentration and can be used as a means and method for validation and monitoring patient compliance, as well as for detecting effective delivery of a drug.

[00174] In another embodiment, spray verification and dosing verification are monitored by measuring the transmission of light from 850 nM to 950 nM across the spray in areas where the droplets are not variably diluted with different inhalation flow rates. obtain. The average signal and the alternating signal from the detector are measured, the optical path (average signal) is calibrated and confirmed, and the spray (alternate signal) is detected. In practice, the alternating signal can be measured by a 100Hz lowpass filter between the detector and the analog converter, sampling the signal 100-500 times per second and averaging and range (maximum and minimum) over a 100mS period. Calculate the difference between the values) and compare these values with the preset values to see if there is proper operation and spraying.

[00175] This method has the following advantages: That is, low power consumption (less than 1 mA relative to the emitter), unaffected by stray light (visible light block of the detector), comparatively tolerant to digital noise or 100 kHz piezo drives with a 100 Hz lowpass filter, average signal level. The advantage is that the light path can be adjusted to adjust the attenuation caused by drug deposition on the LED or detector, and simple hardware with a positive signal measured robustly.

[00176] Also, in this system, the optical signal intensity can be easily adjusted by increasing the power to the emitter when the average signal level drops. In practice, this means using pulse width modulation of the emitter current to adjust the average emitter power. The pulse needs to be at a high rate, such as 100 kHz, and this noise can be removed with a 100 Hz lowpass filter. In nominal operation, a 10% duty cycle of 10mA can be used to achieve an average current of 1mA. The system has the ability to increase the average current to 10 mA and correct the attenuation due to drug deposition up to 10 times.

[00177] In operation with a 950 nM emitter and detector at an angle of ± 20 degrees and 10 mm apart, with 0.5 mA emitter power, 10 K collector resistor, 100 Hz lowpass filter, the average signal output is 2 volts. The peak-to-peak value of the AC component is 4 mV without spray and 40 mV with spray. There may be temporary large peak-to-peak values at the start and end of the spray, which is not intended to be limited and in practice causes large shifts due to bulk attenuation. The size of the resistor here is for the continuous operation of the emitter, not PWM.

[00178] All publications and patent applications cited herein are described herein by reference, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Incorporated into the book.

[00179] Although the present invention has been described with reference to exemplary embodiments, various modifications may be made without departing from the scope of the invention and the elements may be replaced by equivalents. It will be understood by the trader. In addition, many modifications can be made to adapt a particular situation or material to the teaching without departing from its essential scope. Therefore, the present invention is not limited to the specific embodiments disclosed as the best embodiments intended for carrying out the present invention, and the present invention includes all embodiments within the scope of the appended claims. Intended to include.

Claims (20)

An electronically actuated in-line droplet delivery device for delivering a fluid as a flow of droplets to the subject's lung system.
With a housing constructed in a substantially in-line orientation,
A mouthpiece placed at the air outlet of the device and
An air inlet flow element arranged in the air flow at the air inlet of the device,
A small volume drug ampoule arranged within or in the housing containing a drug solution reservoir for receiving a small amount of fluid or in communication with the housing.
An electronically actuated ejector mechanism configured to communicate with the reservoir and generate a discharge stream of the droplets.
With at least one differential pressure sensor located in the housing,
With
The at least one differential pressure sensor is configured to activate the ejector mechanism upon sensing a predetermined pressure change in the mouthpiece, thereby generating a discharge stream of the droplets.
The ejector mechanism includes a piezoelectric actuator and an aperture plate, the aperture plate having a plurality of openings formed through its thickness, and the piezoelectric actuator vibrates the aperture plate to eject the droplets. Generate a flow,
The housing, air inlet flow element, and mouthpiece are configured to facilitate non-turbulent air flow across the outlet side of the aperture plate and provide sufficient air flow through the housing during use.
The ejector mechanism provides at least about 50% of the droplet so that at least about 50% of the mass of the droplet eruption stream is delivered to the subject's lung system in a breathable range during use. Is configured to produce an emission stream of said droplet having an average emission droplet diameter of less than about 6 microns.
In-line droplet delivery device. The small volume drug solution ampoule comprises a storage section including an internal flexible membrane that separates two internal volumes, a first background pressure fluid volume and a drug solution volume, received by the drug solution storage. The described droplet delivery device. The housing and ejector mechanism are oriented so that the outlet side of the aperture plate is perpendicular to the direction of the air flow and the flow of the droplets is discharged parallel to the direction of the air flow. Item 2. The droplet delivery device according to item 1. The housing and the ejector mechanism are oriented so that the outlet side of the aperture plate is parallel to the direction of the airflow and the flow of the droplets is emitted substantially perpendicular to the direction of the airflow. The droplet delivery according to claim 1, wherein the discharge stream of the droplet is directed with respect to the housing so that it changes its trajectory by about 90 degrees and is guided through the housing before being discharged from the housing. apparatus. The droplet delivery device according to claim 1, wherein the air inlet flow element is arranged in the mouthpiece. The droplet delivery device according to claim 5, wherein the air inlet flow element is arranged behind the outlet side of the aperture plate along the direction of the air flow. The droplet delivery device according to claim 5, wherein the air inlet flow element is arranged in-line on the outlet side of the aperture plate or in front of the outlet side along the direction of the air flow. 10. The first aspect of the invention, wherein the air inlet flow element comprises one or more openings that are formed through and configured to increase or decrease internal pressure resistance in the droplet delivery device during use. Droplet delivery device. The droplet delivery device according to claim 8, wherein the air inlet flow element comprises an array of one or more openings. The droplet delivery device according to claim 8, wherein the air inlet flow element includes one or more baffles. The droplet delivery apparatus according to claim 10, wherein the one or more baffles include one or more air flow openings. The droplet delivery device according to claim 1, wherein the aperture plate has a dome shape. The aperture plate is composed of polyetheretherketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultrahigh molecular weight polyethylene (UHMWPE), nickel, nickel cobalt, nickel palladium, palladium, platinum, and alloys thereof. The droplet delivery device according to claim 1, which comprises a material selected from the group consisting of and a combination thereof. The droplet delivery apparatus according to claim 1, wherein one or more of the plurality of openings have different cross-sectional shapes or diameters, thereby providing emission droplets having different average emission droplet diameters. The droplet delivery device according to claim 1, wherein the mouthpiece is detachably coupled to the device. The droplet delivery device according to claim 1, wherein the storage unit is detachably coupled to the housing. The first aspect of the present invention, wherein the storage unit is coupled to the ejector mechanism to form a combined storage unit / ejector mechanism module, and the combined storage unit / ejector mechanism module is detachably coupled to the housing. Droplet delivery device. The droplet delivery device according to claim 1, further comprising a wireless communication module. The droplet delivery device according to claim 1, wherein the device further comprises an infrared transmitter, a photodetector, an additional pressure sensor, and one or more sensors selected from a combination thereof. A method of delivering a therapeutic agent to a subject's lung system as a respiratory flow of droplets to treat a disease, disorder, or condition of the lung.
(A) Through the piezoelectrically actuated droplet delivery apparatus according to claim 1, a step of generating an emission stream of droplets in which at least about 50% has an average emission droplet diameter of less than about 6 μm.
(B) Discharge the droplets into the lungs of the subject so that at least about 50% of the mass of the exhalation of the droplets is delivered to the subject's lung system within a breathable range during use. Steps to deliver to the system to treat lung disease, disorder, or condition, and
How to include.